WO2003048181A1

WO2003048181A1 - 17.alpha. -cyclic esters of 16-methylpregnan-3,20-dione as anti-inflammatory agents

Info

Publication number: WO2003048181A1
Application number: PCT/EP2002/013489
Authority: WO
Inventors: Keith Biggadike
Original assignee: Glaxo Group Limited
Priority date: 2001-12-01
Filing date: 2002-11-28
Publication date: 2003-06-12
Also published as: AU2002356759A1

Abstract

A compound of formula (I): wherein R1 represents hydrogen, chlorine, fluorine, hydroxy or acyloxy OC(O)X, wherein X may be a linear or branched C1-6 alkyl, C3-7 cycloalky, or aryl; R2 represents C3-8 cycloalkyl or C3-8 cycloalkenyl either of which optionally may be substituted by one or more groups selected from C1-6 alkyl, oxo, methylene, halogen or phenyl, which phenyl substituent may be substituted further with one or more groups selected from C1-6 alkyl, C1-6 alkoxy or halogen; R3 represents methyl, which may be in either the α or β configuration or methylene; R4 and R5 are the same or different and each represents hydrogen, a halogen atom or a methyl group; and represents a single or a double bond; and solvates thereof.

Description

7 . ALPHA . -CYCLIC ESTERS OF 16-METHYLPREGNAN-3 , 20-DIONE AS ANTI- INFLAMMATORY

AGENTS

The present invention relates to novel anti-inflammatory and anti-allergic compounds of the pregnane series and to processes for their preparation. The present invention also relates to pharmaceutical formulations containing the compounds and to therapeutic uses thereof, particularly for the treatment of inflammatory and allergic conditions.

Glucocorticosteroids which have anti-inflammatory properties are known and are widely used for the treatment of inflammatory disorders or diseases such as asthma and rhinitis. However, we have identified a novel series of glucocorticosteroids.

Thus, according to one aspect of the invention, there is provided a compound of formula (I)

wherein

Ri represents hydrogen, chlorine, fluorine, hydroxy or acyloxy, OC(O)X, wherein X may be a linear or branched d-₆ alkyl, C_3-7 cycloalky, or aryl; R₂ represents C_3-8 cycloalkyl or C₃.₈ cycloalkenyl either of which optionally may be substituted by one or more groups selected from Cι_-6 alkyl, oxo, methylene, halogen or phenyl, which phenyl substituent may be substituted further with one or more groups selected from Cι_-6 alkyl, Cι_-6 alkoxy or halogen; R₃ represents methyl, which may be in either the α or β configuration or methylene;

R₄ and R₅ are the same or different and each represents hydrogen, a halogen atom or a methyl group; and ^^ represents a single or a double bond; and solvates thereof.

Examples of solvates include hydrates.

References hereinafter to a compound according to the invention includes both compounds of formula (I) and solvates thereof.

It will be appreciated that the invention includes within its scope all stereoisomers of the compounds of formula (I) and mixtures thereof. Preferably, the absolute stereochemistry will be as shown in the representation of compounds of formula (I).

Ri is preferably chlorine, hydrogen, hydroxy or acyloxy, OC(0)X, where X is methyl. We particularly prefer Ri to be chlorine, hydrogen or hydroxy.

Examples of C_3-8 cycloalkyl groups that R₂ may represent include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and substituted derivatives such as methylcyclopropyl (eg 1-methylcyclopropyl), exomethylenecyclobutyl (eg 3- exomethylenecyclobutyl) and tetramethylcyclopropyl (eg 2,2,3,3- tetramethylcyclopropyl).

Examples of C_3-8 cycloalkenyl groups that R₂ may represent include alkenyl groups containing 1 or more double bonds (not being aromatic groups) such as cyclohexenyl eg cyclohex-2,3-enyl.

We prefer R₂ to represent C_3-8 cycloalkyl optionally substituted by one or more methyl and/or halogen groups. We particularly prefer R₂ to represent C_3-6 cycloalkyl, more preferably C_3- cycloalkyl, optionally substituted by one or more methyl or chlorine groups. R₂ is preferably unsubstituted or substituted by at most one methyl or chlorine group. We especially prefer R₂ to be 2,2,3,3-tetramethylcyclopropyl.

We also prefer R₂ to represent C_3-6 cycloalkyl substituted by methylene.

Preferably R₃ represents methyl.

Compounds of formula (I) in which R and R₅, which can be the same or different, each represents hydrogen, halogen or methyl, particularly hydrogen, chlorine or fluorine are preferred. Hydrogen and fluorine are especially preferred.

Preferably, ^====z represents a double bond.

It is to be understood that the present invention covers all combinations of particularly and preferred groups referred to hereinabove.

Preferred compounds of formula (I) include: 9α,21 -Dichloro-11 β-hydroxy-16α-methy-17α-(1 -methylcyclopropyl carbonyl)oxy-pregna-1 ,4-diene-3,20-dione. 9α,21 -Dichloro-11 β-hydroxy-16α-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 11 β,21-Dihydroxy-9α-fluoro-16α-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 11 β,21-Dihydroxy-9α-fluoro-16β-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 11 β,21-Dihydroxy-16α-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 11 β.2.1 -Dihydroxy-16β-methyl-17 -(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 21 -Acetoxy-9α-fluoro-11 β-hydroxy-16β-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 9α-Fluoro-11 β-hydroxy-16β-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 9α-Fluoro-11 β-hydroxy-16α-methyl-17 -(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 9α-Chloro-11 β-hydroxy-16β-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 6α,9 -Difluoro-11 β,21 -dihydroxy-16α-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 6α,9α-Difluoro-11 β-hydroxy-16α-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione

The compounds of formula (I) have potentially beneficial anti-inflammatory or anti-allergic effects, particularly upon topical administration, demonstrated by, for example, their ability to bind to the glucocorticoid receptor and to illicit a response via that receptor. Hence, the compounds of formula (I) are useful in the treatment of inflammatory and/or allergic disorders.

Examples of disease states in which the compounds of the invention have utility include skin diseases such as eczema, psoriasis, allergic dermatitis neurodermatitis, pruritis and hypersensitivity reactions; inflammatory conditions of the nose, throat or lungs such as asthma (including allergen- induced asthmatic reactions), rhinitis (including hayfever), nasal polyps, chronic obstructive pulmonary disease, interstitial lung disease, and fibrosis; inflammatory bowel conditions such as ulcerative colitis and Crohn's disease; and auto-immune diseases such as rheumatoid arthritis.

Compounds of the invention may also have use in the treatment of conjunctiva and conjunctivitis.

It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established conditions. As mentioned above, compounds of formula (I) are useful in human or veterinary medicine, in particular as anti-inflammatory and anti-allergic agents.

There is thus provided as a further aspect of the invention a compound of formula (I) or a physiologically acceptable solvate thereof for use in human or veterinary medicine, particularly in the treatment of patients with inflammatory and/or allergic conditions.

According to another aspect of the invention, there is provided the use of a compound of formula (I) or physiologically acceptable solvate thereof for the manufacture of a medicament for the treatment of patients with inflammatory and/or allergic conditions.

In a further or alternative aspect, there is provided a method for the treatment of a human or animal subject with an inflammatory and/or allergic condition, which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) or physiologically acceptable solvate thereof.

The compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions comprising a compound of formula (I) or physiologically acceptable solvate thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.

Further, there is provided a process for the preparation of such pharmaceutical compositions which comprises mixing the ingredients.

The compounds according to the invention may, for example, be formulated for oral, buccal, sublingual, parenteral, local or rectal administration, especially local administration. Local administration as used herein, includes administration by insufflation and inhalation. Examples of various types of preparation for local administration include ointments, lotions, creams, gels, foams, preparations for delivery by transdermal patches, powders, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (e.g. eye or nose drops), solutions/suspensions for nebulisation, suppositories, pessaries, retention enemas and chewable or suckable tablets or pellets (e.g. for the treatment of aphthous ulcers) or liposome or microencapsulation preparations.

Ointments, creams and gels, may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents. Such bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol. Thickening agents and gelling agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, woolfat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents, suspending agents or preservatives.

Spray compositions may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant. Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain a compound of formula (I) and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, especially 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane or a mixture thereof. The aerosol composition may optionally contain additional formulation excipients well known in the art such as surfactants e.g. oleic acid or lecithin and cosolvents e.g. ethanol.

Advantageously, the formulations of the invention may be buffered by the addition of suitable buffering agents.

Capsules and cartridges for use in an inhaler or insufflator, of for example gelatine, may be formulated containing a powder mix for inhalation of a compound of the invention and a suitable powder base such as lactose or starch. Each capsule or cartridge may generally contain between 20μg-10mg of the compound of formula (I). Alternatively, the compound of the invention may be presented without excipients such as lactose.

The proportion of the active compound of formula (I) in the local compositions according to the invention depends on the precise type of formulation to be prepared but will generally be within the range of from 0.001 to 10% by weight. Generally, however for most types of preparations advantageously the proportion used will be within the range of from 0.005 to 1% and preferably 0.01 to 0.5%. However, in powders for inhalation or insufflation the proportion used will be within the range of from 0.1 to 5%.

Aerosol formulations are preferably arranged so that each metered dose or "puff of aerosol contains 20μg-2000μg, preferably about 20μg-500μg of a compound of formula (l). Administration may be once daily or several times daily, for example 2, 3, 4 or 8 times, giving for example 1 , 2 or 3 doses each time. The overall daily dose with an aerosol will be within the range 100μg- 10mg preferably, 200μg-2000μg. The overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double those with aerosol formulations. Topical preparations may be administered by one or more applications per day to the affected area; over skin areas occlusive dressings may advantageously be used. Continuous or prolonged delivery may be achieved by an adhesive reservoir system.

For internal administration the compounds according to the invention may, for example, be formulated in conventional manner for oral, parenteral or rectal administration. Formulations for oral administration include syrups, elixirs, powders, granules, tablets and capsules which typically contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, wetting agents, suspending agents, emulsifying agents, preservatives, buffer salts, flavouring, colouring and/or sweetening agents as appropriate. Dosage unit forms are, however, preferred as described below.

Preferred forms of preparation for internal administration are dosage unit forms i.e. tablets and capsules. Such dosage unit forms contain from 0.1 mg to 20mg preferably from 2.5 to 10mg of the compounds of the invention.

The compounds according to the invention may in general may be given by internal administration in cases where systemic adreno-cortical therapy is indicated.

In general terms preparations, for internal administration may contain from 0.05 to 10% of the active ingredient dependent upon the type of preparation involved. The daily dose may vary from 0.1 mg to 60mg, e.g. 5-30mg, dependent on the condition being treated, and the duration of treatment desired.

Slow release or enteric coated formulations may be advantageous, particularly for the treatment of inflammatory bowel disorders.

The pharmaceutical compositions according to the invention may also be used in combination with another therapeutically active agent, for example, a β₂ adrenoreceptor agonist, an anti-histamine or an anti-allergic. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together with another therapeutically active agent, for example, a β₂-adrenoreceptor agonist, an anti-histamine or an anti-allergic.

Examples of β₂-adrenoreceptor agonists include salmeterol (eg as racemate or a single enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline and salts thereof, for example the xinafoate salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol. Long-acting β₂-adrenoreceptor agonists are preferred, especially those having a therapeutic effect over a 24 hour period such as salmeterol or formoterol.

Preferred long acting β₂-adrenoreceptor agonists include those described in WO 0266 422A.

Especially preferred long-acting β₂-adrenoreceptor agonists include compounds of formula(X):

or a salt or solvate thereof, wherein: m is an integer of from 2 to 8; n is an integer of from 3 to 11 , with the proviso that m + n is 5 to 19,

R¹¹ is -XS0₂NR¹⁶R¹⁷ wherein X is -(CH₂)_P- or C_2-6 alkenylene; R¹⁶ and R¹⁷ are independently selected from hydrogen, Cι_-6alkyl, C_3- rcycloalkyl, C(O)NR¹⁸R¹⁹, phenyl, and phenyl (C_1-4alkyl)-, or R¹⁶ and R¹⁷, together with the nitrogen to which they are bonded, form a 5-,

6-, or 7- membered nitrogen containing ring, and R¹⁶ and R¹⁷ are each optionally substituted by one or two groups selected from halo, Cι_-6alkyl, C_1-6haloalkyl, C^alkoxy, hydroxy-substituted C_1-6alkoxy, -CO₂R¹⁸, - S0₂NR¹⁸R¹⁹, -CONR¹⁸R¹⁹, -NR¹⁸C(O)R¹⁹, or a 5-, 6- or 7-membered heterocylic ring;

R¹⁸ and R¹⁹ are independently selected from hydrogen, Cι_-6alkyl, C_3-6cycloalkyl, phenyl, and phenyl (Cι_-4alkyl)-; and p is an integer of from 0 to 6, preferably from 0 to 4;

R¹² and R¹³ are independently selected from hydrogen, Cι_-6alkyl, Cι_-6alkoxy, halo, phenyl, and C_1-6haloalkyl; and

R¹⁴ and R¹⁵ are independently selected from hydrogen and Cι_-4alkyl with the proviso that the total number of carbon atoms in R¹⁴ and R¹⁵ is not more than 4.

Examples of anti-histamines include methapyrilene or loratadine.

Other suitable combinations include, for example, other anti-inflammatory agents eg. NSAIDs (eg. PDE4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2a agonists)) or antiinfective agents (eg. antibiotics, antivirals).

Of particular interest is use of the compounds of formula (I) in combination with a phosphodiesterase 4 (PDE4) inhibitor. The PDE4-specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family as well as PDE4. Generally it is preferred to use a PDE4 inhibitor which has an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity. For the purposes of this disclosure, the cAMP catalytic site which binds R and S rolipram with a low affinity is denominated the "low affinity" binding site (LPDE 4) and the other form of this catalytic site which binds rolipram with a high affinity is denominated the "high affinity" binding site (HPDE 4). This term "HPDE4" should not be confused with the term "hPDE4" which is used to denote human PDE4. Initial experiments were conducted to establish and validate a [³H]-rolipram binding assay. Details of this work are given in the Binding Assays described in detail below.

The preferred PDE4 inhibitors of use in this invention will be those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity. Another way to state this is that the preferred compounds will have an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity.

A further refinement of this standard is that of one wherein the PDE4 inhibitor has an IC50 ratio of about 0.1 or greater; said ratio is the ratio of the IC50 value for competing with the binding of 1 nM of [^HjR-rolipram to a form of PDE4 which binds rolipram with a high affinity over the IC50 value for inhibiting the PDE4 catalytic activity of a form which binds rolipram with a low affinity using 1 μM[³H]-cAMP as the substrate.

Examples of useful PDE4 inhibitors are:

(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2- pyrrolidone; (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2- pyrrolidone;

3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N2-cyano-S-methyl- isothioureido]benzyl)-2-pyrrolidone; cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyI)cyclohexan-1-carboxylic acid]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1- ol];

(R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2- ylidenejacetate; and (S)-(-)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2- ylidenejacetate.

Most preferred are those PDE4 inhibitors which have an IC50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0. Preferred compounds are cis 4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-1 -carboxylic acid, 2-carbomethoxy-4-cyano-4-(3- cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1 -one and c/^'s-[4- cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]; these are examples of compounds which bind preferentially to the low affinity binding site and which have an IC50 ratio of 0.1 or greater. Other compounds of interest include:

Compounds set out in U.S. patent 5,552,438 issued 03 September, 1996; this patent and the compounds it discloses are incorporated herein in full by reference. The compound of particular interest, which is disclosed in U.S. patent 5,552,438, is c/s-4-cyano-4-[3- (cyclopentyloxy)-4- methoxyphenyl]cyclohexane-1 -carboxylic acid (also known as cilomalast) and its salts, esters, pro-drugs or physical forms; AWD-12-281 from Astra (Hofgen, N. et_aj. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98); a 9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering- Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787; Parke-Davis/Warner-Lambert); a benzodioxole derivative Kyowa Hakko disclosed in WO 9916766; V-11294A from Napp (Landells, L.J. et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12(Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a pthalazinone (WO 9947505) from Byk-Gulden; or a compound identified as T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther,1998, 284(1 ): 162).

Phosphodiesterase and Rolipram Binding Assays Assay method 1A Isolated human monocyte PDE4 and hrPDE (human recombinant PDE4) was determined to exist primarily in the low affinity form. Hence, the activity of test compounds against the low affinity form of PDE4 can be assessed using standard assays for PDE4 catalytic activity employing 1 μM [³H]cAMP as a substrate (Torphy et al.. J. of Biol. Chem., Vol. 267, No. 3 pp1798-1804, 1992).

Rat brain high speed supernatants were used as a source of protein and both enantiomers of [³H]-rolipram were prepared to a specific activity of 25.6 Ci/mmol. Standard assay conditions were modified from the published procedure to be identical to the PDE assay conditions, except for the last of the cAMP: 50mM Tris HCI (pH 7.5), 5 mM MgCl2, 50 μM 5'-AMP and 1 nM of [³H]-rolipram (Torphy et al.. J. of Biol. Chem., Vol. 267, No. 3 pp1798-1804, 1992). The assay was run for 1 hour at 30° C. The reaction was terminated and bound ligand was separated from free ligand using a Brandel cell harvester. Competition for the high affinity binding site was assessed under conditions that were identical to those used for measuring low affinity PDE activity, expect that [³H]-cAMP was not present.

Assay method 1 B Measurement of Phosphodiesterase Activity

PDE activity was assayed using a [³H]cAMP SPA or [³H]cGMP SPA enzyme assay as described by the supplier (Amersham Life Sciences). The reactions were conducted in 96-well plates at room temperature, in 0.1 ml of reaction buffer containing (final concentrations): 50 mM Tris-HCI, pH 7.5, 8.3 mM MgCI₂, 1.7 mM EGTA, [³H]cAMP or [³H] cGMP (approximately 2000 dpm/pmol), enzyme and various concentrations of the inhibitors. The assay was allowed to proceed for 1 hr and was terminated by adding 50 μl of SPA yttrium silicate beads in the presence of zinc sulfate. The plates were shaken and allowed to stand at room temperature for 20 min. Radiolabeled product formation was assessed by scintillation spectrometry.

[³H1R-rolipram binding assay

The [³H]R-rolipram binding assay was performed by modification of the method of Schneider and co-workers, see Nicholson, et al.. Trends Pharmacol. Sci., Vol. 12, pp.19-27 (1991) and McHale et al.. Mol. Pharmacol., Vol. 39, 109-113 (1991 ). R-Rolipram binds to the catalytic site of PDE4 see Torphy et al.. Mol. Pharmacol., Vol. 39, pp. 376-384 (1991 ). Consequently, competition for [ H]R-rolipram binding provides an independent confirmation of the PDE4 inhibitor potencies of unlabeled competitors. The assay was performed at 30°C for 1 hr in 0.5 μl buffer containing (final concentrations): 50 mM Tris-HCI, pH 7.5, 5 mM MgCI₂, 0.05% bovine serum albumin, 2 nM [³H]R-rolipram (5.7 x 104 dpm/pmol) and various concentrations of non- radiolabeled inhibitors. The reaction was stopped by the addition of 2.5 ml of ice-cold reaction buffer (without [³H]-R-rolipram) and rapid vacuum filtration (Brandel Cell Harvester) through Whatman GF/B filters that had been soaked in 0.3% polyethylenimine. The filters were washed with an additional 7.5 ml of cold buffer, dried, and counted via liquid scintillation spectrometry.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable solvate thereof together with a PDE4 inhibitor.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.

The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.

The compounds of formula (I) and solvates thereof may be prepared by the methodology described hereinafter, constituting a further aspect of this invention. A process (A) according to the invention for preparing a compound of formula (I) comprises ring-opening of an epoxide compound of formula (II)

wherein R-i, R₂, R₃, Rsand are as defined above.

In this process the compound of formula (II) may be reacted with, for example, an acid eg hydrochloric acid.

Compounds of formula (II) may be prepared from the corresponding 17α- hydroxyl derivative of formula (III):

wherein R-i, R₃, R₅ and are as defined above, by acylation with a carboxylic acid of formula (IV) or an activated derivative thereof:

(IV) where R₂ is defined above. Examples of activated derivatives include activated esters eg acid anhydrides and acid halides especially the acid chloride.

This reaction may be performed under standard conditions eg by reaction with an acid chloride in the presence of triethylamine and dimethylaminopyridine (DMAP), in an organic solvent eg dichloromethane.

Compounds of formula (III) may be prepared in accordance with procedures described by Draper et al., Tetrahedron (1999), 55, 3355-3364.

Compounds of formula (II) are new and form an aspect of the invention.

An alternative process (B) according to the invention for preparing a compound of formula (I) comprises deprotection of a compound of formula

(V):

wherein R_{1 ;} R₂, R₃, R , R₅ and ^{z r} are as defined above, and P is a suitable hydroxyl protecting group. For the preparation of compounds of formula (I) where Ri is a hydroxyl group this hydroxyl group would also be suitably protected in compound (V).

Hydroxyl groups may be protected using any conventional hydroxyl protecting group, for example, as described in Protective Groups in Organic Chemistry, Ed. J.F.W. McOmie (Plenum Press, 1973) or Protective Groups in Organic Synthesis by Theodora W. Green (John Wiley and Sons, 1991). Examples of suitable hydroxyl protecting groups include groups selected from alkyl (e.g. t-butyl or methoxymethyl), aralkyl (e.g. benzyl, diphenylmethyl or triphenylmethyl), heterocyclic groups such as tetrahydropyranyl, acyl (e.g. acetyl or benzoyl) and silyl groups such as trialkylsilyl (e.g. t- butyldimethylsilyl). The hydroxyl protecting groups may be removed by conventional techniques. Thus, for example alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g. by hydrolysis under-acidic or basic conditions. Aralkyl groups such as triphenylmethyl may be similarly be removed by solvolysis, e.g. by hydrolysis under acidic conditions. Aralkyl groups such as benzyl may be cleaved by hydrogenolysis in the presence of a Noble metal catalyst such as palladium-on-charcoal.

Compounds of formula (V) form an aspect of the invention.

Compounds of formula (V) may be prepared from the corresponding 17α- hydroxyl derivative of formula (VI):

wherein R-i, R₃, R₄, R₅ and ^{= r=::} are as defined above by acylation with a carboxylic acid of formula (IV) or an activated derivative thereof. When R-i is a hydroxyl group it should be suitably protected. Examples of activated derivatives include activated esters eg acid anhydrides and acid halides especially the acid chloride. This reaction may be performed under standard conditions eg by reaction with an acid chloride in the presence of triethylamine and dimethylaminopyridine (DMAP), in an organic solvent eg dichloromethane. Compounds of formula (VI) are prepared by protection of compounds of formula (VII):

wherein R-i, R₃, R₄, R₅ and are as defined above, using for example, mothod such as those described by Kooreman et al., Synthetic

Communications (1971 ), 1 , 81-87 and references thereon.

Compounds of formula (VII) are either known or may be prepared by standard methodology.

A further method (C) for preparing compounds of formula (I) comprises rearrangement of 21 -esters of formula (VIII):

wherein R₂, R₃, R₄, R5 and are as defined above, by treatment for example, with lithium dimethyl cuprate as described by Phillips et al.. DE 73- 2340591.

Compounds of formula (VIII) are known or can be prepared by selective acylation of compounds of formula (IX):

wherein R₃, R₄, R₅ and are as defined above, using standard methodology as described for example by Kooreman et al.. Synthetic Communications (1971 ), 1 , 81-87 and references therein.

Compounds of formula (IX) are known or can be prepared by standard methodology.

An alternative process (D) according to the invention for preparing a compound of formula (I) comprises hydrolysis of cyclic orthoesters of formula (X):

wherein R₂, R₃, R₄, R₅ and are as defined above and R₆ is a Cι to C₆ alkyl group, preferably methyl or ethyl, using for example, AICI₃ in aqueous methanol as described by Ueno et a.., J Med Chem, (1991), 34, 2468-2473.

Compounds of formula (X) may be prepared by reaction of compounds of formula (IX) with ortho esters of formula (XI) which are either known or may be prepared by standard methodology. R₂-(OR₆)₃

(XI) Solvates of compounds of formula (I) which are not physiologically acceptable may be useful as intermediates in the preparation of compounds of formula (I) or physiologically acceptable solvates thereof.

The advantages of compounds of formula (I) and/or solvates thereof include the fact that the substances demonstrate good anti-inflammatory properties, with predictable pharmacokinetic and pharmacodynamic behaviour. They also have an attractive side-effect profile, demonstrated, for example, by increased selectivity for the glucocorticoid receptor over the progesterone receptor and/or increased selectivity for glucocorticoid receptor mediated transrepression over transactivation, and are compatible with a convenient regime of treatment in human patients.

The following non-limiting Examples illustrate the invention:

EXAMPLES General

Chromatographic purification was performed either using pre-packed Bond Elut SPE silica gel cartridges available commercially from Varian or by flash chromatography on pre-packed Biotage silica columns. The Bond Elut cartridges were pre-conditioned with dichloromethane prior to use. LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1 % HC0₂H and 0.01 M ammonium acetate in water (solvent A), and 0.05% HCO₂H 5% water in acetonitrile (solvent B), using the following elution gradient 0-0.7 min 0%B, 0.7-4.2 min 100%B, 4.2-5.3 min 0%B, 5.3-5.5 min 0%B at a flow rate of 3 ml/min. The mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).

Intermediates Intermediate 1 : 21-Chloro-9β,11 β-epoxy-16α-methyl-17α-(1- methylcvclopropylcarbonyl)oxy-preqna-1 ,4-diene-3,20-dione To a stirred and cooled (ice) solution of 21-chloro-9β,11 β-epoxy-16 -methyl- 17α-hydroxy-pregna-1 ,4-diene-3,20-dione (687mg, 1.76mmol) (prepared by methods analogous to those described in Draper et al, (1999) Tetrahedron, 55, 3355-3364) and 4-dimethylaminopyridine (430mg, 3.52mmol) in dichloromethane (10ml) was added a solution of triethylamine (0.27ml, 1.94mmol) and 1-methylcyclopropanecarbonyl chloride (250mg, 2.1 mmol) in dichloromethane (2ml). The mixture was stirred under nitrogen for 18h and then washed successively with 2M hydrochloric acid (2x20ml), aqueous sodium bicarbonate (2x20ml), brine (20ml) and dried through a hydrophobic frit and evaporated. The residue was purified on a Bond Elut cartridge (10g) eluting with dichloromethane followed by 5% ethyl acetate in dichloromethane to yield the title compound as a white foam (445mg): LCMS retention time 3.62 min.

Intermediate 2: 21-Chloro-9β.11 β-epoxy-16α-methyl-17α-(2,2,3,3- tetramethvcvclopropylcarbonyl)oxy-pregna-1 ,4-diene-3.20-dione Prepared using methods similar to that described for Intermediate 1. LCMS retention time 3.95 min.

Intermediate 3: 21-Acetoxy-17α-hvdroxy-16α-methyl-11 β-trimethylsilyloxy - pregna-1 ,4-diene-3,20-dione

To a solution of 21-acetoxy-11 β,17α-dihydroxy-16α-methyl- pregna-1 ,4-diene- 3,20-dione (370mg, 0.89mmol) in anhydrous pyridine (3ml) was added chlorotrimethylsilane (0.23ml, 1.8mmol) and the solution was stirred under nitrogen for 22h at 21 °C. Dichloromethane (20ml) was added and the solution was washed successively with water (2x20ml), 2N hydrochloric acid (20ml) and water (20ml). Cyclohexane (20ml) was added and the solution was loaded onto a Bond Elut cartridge (10g). This was eluted with a stepwise gradient of cyclohexane/ethyl acetate mixtures 10:1 to 3:1. 3:1 cyclohexane/ethyl acetate fractions contained product and were combined and evaporated to give the title compound as a white solid (227mg). LCMS retention time 3.88 min MH⁺ 489. Intermediate 4: 21-Acetoxy-16α-methyl-17α-(2,2,3,3- tetramethylcvclopropylcarbonyl)oxy-11 β-trimethylsilyloxy-preqna-1 ,4-diene- 3,20-dione

To a solution of 21-Acetoxy-17α-hydroxy-16α-methyl-11β-trimethylsilyloxy - pregna-1 ,4-diene-3,20-dione (222mg, 0.45mmol) in anhydrous dichloromethane (7ml) was added a solution of tetramethycyclopropanecarbonyl chloride (290mg, 1.8mmol) in anhydrous dichloromethane (1.8ml) and a solution of 4-N,N-dimethylaminopyridine (165mg, 1.35mmol) in anhydrous dichloromethane (1.35ml). The solution was stirred for 2 days at 21 °C. The solution was then washed successively with 2N hydrochloric acid (5ml), saturated sodium bicarbonate (5ml) and water (5ml) and concentrated to low volume. The solution was purified on a Bond Elut cartridge (5g) eluting with a stepwise gradient of cyclohexane/ethyl acetate mixtures 10:1 to 1 :1. The 6:1 cyclohexane/ethyl acetate fraction was evaporated to give the title compound as a white solid. LCMS retention time 4.42 min, MH⁺ 613.

Intermediate 5: 21-Acetoxy-17α-hvdroxy-16β-methyl-11 β-trimethylsilyloxy - preqna-1 ,4-diene-3,20-dione Prepared using methods similar to that described for Intermediate 3. LCMS retention time 3.89 min, MH⁺ 489.

Intermediate 6: 21-Acetoxy-16β-methyl-17α-(2,2,3,3- tetramethylcvclopropylcarbonyl)oxy-11 β-trimethylsilyloxy-pregna-1 ,4-diene- 3,20-dione

Prepared using methods similar to that described for Intermediate 4. LCMS retention time 4.52 min, MH⁺ 613.

Intermediate 7: 21-Acetoxy-6α,9α-difluoro-17α-hvdroxy-16α-methyl-11 β- trimethylsilyloxy-preqna-1 ,4-diene-3,20-dione

Prepared using methods similar to that described for Intermediate 3. LCMS retention time 3.70 min, MH⁺ 525.

Intermediate 8: 21 -Acetoxy-6α.9α-difluoro-16α-methyl-17α-(2.2.3.3- tetramethylcvclopropylcarbonvOoxy-11 β-trimethylsilyloxy-preqna-1 ,4-diene- 3,20-dione Prepared using methods similar to that described for Intermediate 4 except that triethylamine was used as an additional base. LCMS retention time 4.23 min, MH⁺ 649.

Intermediate 9: 9α-Fluoro-17α-hvdroxy-16β-methyl-11 β-trimethylsilyloxy- preqna-1 ,4-diene-3,20-dione

Prepared using methods similar to that described for Intermediate 3. LCMS retention time 3.73 min, MH⁺ 449.

Intermediate 10: 9α-Fluoro-16β-methyl-17α-(2,2,3,3- tetramethylcvclopropylcarbonyl)oxy-11 β-trimethylsilyloxy-preqna-1 ,4-diene-

3.20-dione

Prepared using methods similar to that described for Intermediate 4.

LCMS retention time 4.41 min, MH⁺ 573.

Intermediate 11 : 9α-Fluoro-17α-hvdroxy-16α-methyl-11 β-trimethylsilyloxy- preqna-1 ,4-diene-3,20-dione

Prepared using methods similar to that described for Intermediate 3.

LCMS retention time 3.73 min. MH⁺ 449.

Intermediate 12: 9α-Fluoro-16α-methyl-17α-(2,2,3,3- tetramethylcvclopropylcarbonvPoxy -11 β-trimethylsilyloxy-pregna-1 ,4-diene-

3.20-dione

Prepared using methods similar to that described for Intermediate 4. LCMS retention time 4.36 min, MH⁺ 573.

Intermediate 13: 9α-Chloro-17α-hvdroxy-16β-methyl-11 β-trimethylsilyloxy- preqna-1 ,4-diene-3,20-dione

Prepared using methods similar to that described for Intermediate 3. LCMS retention time 3.92 min, MH⁺ 465.

Intermediate 14: 9α-Chloro-16β-methyl-17α-(2.2.3.3- tetramethylcvclopropylcarbonvPoxy -11 β-trimethylsilyloxy-preqna-1 ,4-diene- 3.20-dione Prepared using methods similar to that described for Intermediate 4. +

LCMS retention time 4.53 min, MH 589.

Intermediate 15: 21-Acetoxy-9α-fluoro-16α-methyl-17α-(2,2,3,3- tetramethylcvclopropylcarbonyl)oxy-11 β-trimethylsilyloxy-preqna-1 ,4-diene- 3,20-dione

Prepared using methods similar to that described for Intermediate 4. LCMS retention time 4.26 min, MH⁺ 631.

Intermediate 16: 21-Acetoxy-9α-fluoro-16β-methyl-17α-(2.2.3.3- tetramethylcvclopropylcarbonyl)oxy-11 β-trimethylsilyloxy-preqna-1 ,4-diene- 3.20-dione

Prepared using methods similar to that described for Intermediate 4. LCMS retention time 4.37 min, MH⁺ 631.

Intermediate 17: 6α,9α-Difluoro-17α-hvdroxy-16α-methyl-11 β- trimethylsilyloxy-preqna-1 ,4-diene-3,20-dione Prepared using methods similar to that described for Intermediate 3. LCMS retention time 3.73 min. MH⁺ 467.

Intermediate 18: 6α.9α-Difluoro-16α-methyl-17α-(2.2.3.3- tetramethylcvclopropylcarbonvDoxy -11 β-trimethylsilyloxy-preqna-1 ,4-diene-

3.20-dione

Prepared using methods similar to that described for Intermediate 4.

LCMS retention time 4.37 min, MH⁺ 591

Examples

Example 1 : 9α,21 -Dichloro-11 β-hvdroxy-16α-methyl-17α-(1 - methylcvclopropylcarbonyl)oxy-preqna-1 ,4-diene-3,20-dione Concentrated hydrochloric acid (1.5ml) was added dropwise to a stirred and cooled solution of Intermediate 1 (445mg, 0.94mmol) in dichloromethane (10ml) followed by glacial acetic acid (2ml) keeping the internal temperature at 0 °C. The reaction was stirred under nitrogen for 18h and then poured into water (20ml) and the organic phase separated. The aqueous phase was then washed with dichloromethane (2x25ml) and the combined organic extracts were washed with 1 M sodium carbonate solution (20ml), 0.5M sodium carbonate solution (20ml) dried through a hydrophobic frit and evaporated. The residue was purified using a Bond Elut cartridge (10g) eluting with dichloromethane followed by 5% ethyl acetate in dichloromethane to yield the title compound as a white solid (260mg): LCMS retention time 3.62 min, MH⁺ 509, 511 , 513.

Example 2: 9 .21 -Dichloro-11 β-hvdroxy-16α-methyl-17α-(2.2.3.3- tetramethylcvclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione Prepared from Intermediate 2 using a method similar to that described for Examplel . LCMS retention time 3.95 min, MH⁺ 551 ,553, 555.

Example 3: 11 ,21-Dihvdroxy-9α-fluoro-16α-methyl-17α-(2,2,3,3- tetramethylcvclopropylcarbonyl)oxy-pregna-1.4-diene-3.20-dione To a solution of Intermediate 15 (95mg. 0.15mmol) in methanol (11ml) was added 3M hydrochloric acid (2ml) and the solution was stirred at 21°C for 65h. Aqueous sodium acetate solution was added to pH6 and most of the methanol was evaporated. The resulting suspension was extracted with dichloromethane (10ml) and the organic phase was separated, concentrated and loaded onto Bond Elut cartridge (5g). This was eluted with a stepwise gradient of cyclohexane/ethyl acetate mixtures 9:1 to 1 :1. The 3:2 and 1 :1 cyclohexane/ethyl acetate fractions were evaporated to give the title compound as a white solid (18mg). LCMS retention time 3.61 min, MH⁺ 517.

Example 4: 11 β.21-Dihvdroxy-9α-fluoro-16β-methyl-17α-(2,2.3.3- tetramethylcvclopropylcarbonyl)oxy-preqna-1.4-diene-3,20-dione Prepared from Intermediate 16 (175mg) using a method similar to that described for Example 3. The product (57mg) was isolated by flash chromatography on a Biotage prepacked column (9g) eluting with a 2:1 mixture of cyclohexane and ethyl acetate. LCMS retention time 3.66 min, MH⁺ 517.

Example 5: 11β.21-Dihvdroxy-16α-methyl-17α-(2.2.3,3- tetramethylcvclopropylcarbonv0oxy-preqna-1.4-diene-3,20-dione Prepared from Intermediate 4 using a method similar to that described for Example 3. LCMS retention time 3.68 min, MH⁺ 499.

Example 6: 11 β.21-Dihvdroxy-16β-methyl-17α-(2.2,3.3- tetramethylcvclopropylcarbonyl)oxy-pregna-1 ,4-diene-3.20-dione

Prepared from Intermediate 6 using a method similar to that described for Example 3. LCMS retention time 3.74 min, MH⁺ 499.

Example 7: 21-Acetoxy-9α-fluoro-11 β-hvdroxy-16β-methyl-17α-(2.2.3,3- tetramethylcvclopropylcarbonv0oxy-preqna-1 ,4-diene-3,20-dione

Prepared from Intermediate 16 (175mg) as in Example 4. Appropriate fractions were combined and evaporated to give Example 7 (13mg). LCMS retention time 3.90 min, MH⁺ 559.

Example 8: 9α-Fluoro-11 β-hvdroxy-16β-methyl-17α-(2,2,3,3- tetramethylcvclopropylcarbonyl)oxy-preqna-1 ,4-diene-3,20-dione Prepared from Intermediate 10 using a method similar to that described for Example 3. LCMS retention time 3.89 min, MH⁺ 501.

Example 9: 9α-Fluoro-11 β-hvdroxy-16α-methyl-17α-(2,2,3,3- tetramethylcvclopropylcarbonv0oxy-preqna-1 ,4-diene-3,20-dione Prepared from Intermediate 12 using a method similar to that described for Example 3. LCMS retention time 3.81 min, MH⁺ 501.

Example 10: 9α-Chloro-11 β-hydroxy-16β-methyl-17α-(2.2.3.3- tetramethylcvclopropylcarbonyl)oxy-preqna-1 ,4-diene-3.20-dione Prepared from Intermediate 14 using a method similar to that described for Example 3. LCMS retention time 3.84 min, MH⁺ 517, 519.

Example 11 : 6α.9α-Difluoro-11 β.21-dihvdroxy-16α-methyl-17α-(2.2.3.3- tetramethylcvclopropylcarbonvπoxy-preqna-1 ,4-diene-3.20-dione Prepared from Intermediate 8 using a method similar to that described for Example 3. LCMS retention time 3.57 min, MH⁺ 535. Example 12: 6α,9α-Difluoro-11 β-hvdroxy-16α-methyl-17 -(2,2,3,3- tetramethylcvclopropylcarbonyl)oxy-preqna-1 ,4-diene-3,20-dione Example 12 was prepared from Intermediate 18 using a method similar to that described for Example 3. LCMS retention time 3.91 min, MH⁺ 519.

Pharmacological Activity

Pharmacological activity may be assessed in functional in vitro assays of glucocorticoid agonist activity.

The functional assay based on that described by K.P.Ray et al., Biochem J. (1997), 328, 707-715 provides a measure of transrepressive activity of a glucocorticoid agonist. A549 cells stably transfected with a reporter gene containing the NF-κB responsive elements from the ELAM gene promoter coupled to sPAP (secreted alkaline phosphatase) are treated with test compounds at appropriate doses for 1 hour at 37°C. The cells are then stimulated with tumour necrosis factor (TNF, 10ng/ml) for 16 hours, at which time the amount of alkaline phosphatase produced is measured by a standard colourimetric assay. Dose response curves are constructed from which EC50 values may be estimated.

The EC₅₀ values for compounds of Examples 1 to 6 and 8, 9, 11 and 12 in this assay were determined to be <1 nM. The EC₅₀ value for Example 7 was 2nM.

The functional assay based on that described by R.J.H. Austin et al., Eur Resp J. (2002 - in press) measures the ability of compounds to directly transactivate gene expression. A549 cells stably transfected with a reporter gene containing the glucocorticoid responsive region of the mouse mammary tumour virus long terminal repeat (MMTV-LTR) coupled to renilla luciferase were treated with test compounds at appropriate doses for 6 hour at 37°C. The amount of luciferase activity present within the cells is then determined by measuring the light emitted following incubation with a suitable substrate. Dose response curves were constructed from which EC₅₀ values were estimated and from which maximal responses are calculated relative to Dexamethasone (100%).

Examples 2 to 12 showed maximal responses of <20% in this assay.

Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims.

The patents and patent applications described in this application are herein incorporated by reference.

Claims

1. A compound of formula (I):

wherein

Ri represents hydrogen, chlorine, fluorine, hydroxy or acyloxy OC(O)X, wherein X may be a linear or branched C-i-e alkyl, C₃. cycloalky, or aryl;

R₂ represents C_3-8 cycloalkyl or C_3-8 cycloalkenyl either of which optionally may be substituted by one or more groups selected from Cι_-6 alkyl, oxo, methylene, halogen or phenyl, which phenyl substituent may be substituted further with one or more groups selected from Cι-β alkyl, C-ι-6 alkoxy or halogen;

R₃ represents methyl, which may be in either the α or β configuration or methylene;

R and R₅ are the same or different and each represents hydrogen, a halogen atom or a methyl group; and represents a single or a double bond; and solvates thereof.

2. A compound as claimed in claim 1 where Ri represents chlorine, hydrogen, hydroxy or acyloxy, OC(0)X, where X is methyl.

3. A compound as claimed in claim 1 or claim 2 wherein R₂ represents cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and substituted derivatives such as methylcyclopropyl, exomethylenecyclobutyl and tetramethylcyclopropyl.

4. A compound as claimed in any one of claims 1 to 3 which is: 9α,21 -Dichloro-11 β-hydroxy-16 -methy-17α-(1-methylcyclopropyl carbonyl)oxy-pregna-1 ,4-diene-3,20-dione.

9α,21 -Dichloro-11 β-hydroxy-16α-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 11 β,21 -Dihydroxy-9α-fluoro-16α-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 11 β,21 -Dihydroxy-9α-fluoro-16β-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 11 β,21-Dihydroxy-16α-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 11 β,21-Dihydroxy-16β-methyl-17 -(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 2.1 -Acetoxy-9α-fluoro-11 β-hydroxy-16β-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 9α-Fluoro-11 β-hydroxy-16β-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 9 -Fluoro-11 β-hydroxy-16α-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 9α-Chloro-11 β-hydroxy-16β-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione 6α,9α-Difluoro-11β,21-dihydroxy-16α-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione, or 6α,9α-Difluoro-11 β-hydroxy-16α-methyl-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-pregna-1 ,4-diene-3,20-dione

5. A compound of formula (I) as defined in any one of claims 1 to 4 or a physiologically acceptable solvate thereof for use in veterinary or human medicine.

6. Use of a compound of formula (I) as defined in any one of claims 1 to 4 or a physiologically acceptable solvate thereof for the manufacture of a medicament for the treatment of inflammatory and/or allergic conditions.

7. A pharmaceutical composition comprising a compound of formula (1) as defined in any one of claims 1 to 4 or a physiologically acceptable solvate thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.

8. A pharmaceutical aerosol formulation comprising a compound of formula (I) as defined in any one of claims 1 to 4 or a physiologically acceptable solvate thereof, and a fluorocarbon or hydrogen-containing chlorofluoro carbon as propellant, optionally in combination with a surfactant and/or a cosolvent.

9. A pharmaceutical composition according to claim 7 or 8 which further comprises another therapeutically active agent.

10. A pharmaceutical composition according to claim 9 in which said another therapeutically active agent is a β₂-adrenoreceptor agonist.

11. A method for the treatment of a human or animal subject with an anti- inflammatory and/or allergic condition, which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) as defined in any one of claims 1 to 4 or a physiologically acceptable solvate thereof.

12. A compound of formula (II)

wherein R_{1 (} R₂, R₃, R₅ and — are as defined in any one of claims 1 to 4.

13. A compound of formula (V)

wherein Ri, R₂, R3, R4, R5 and are as defined in any one of claims 1 to

4 and P is a suitable hydroxyl protecting group.

14. A process for preparing a compound of formula (I) as defined in any one of claims 1 to 4 which comprises ring-opening of an epoxide compound of formula (II)

wherein R_{1 ;} R₂, R3, R5 and are as defined in any one of claims 1 to 4.

15. A process for the preparation of a compound of formula (II) as defined in claim 12 from the corresponding 17α-hydroxyl derivative of formula (III):

by acylation with a carboxylic acid of formula (IV) or an activated derivative thereof:

R₂COOH (IV) wherein R-i, R₂, R₃, R₅ and are as defined in claim 12.

16. A process for preparing a compound of formula (I) as defined in anyone of claims 1 to 4 which comprises deprotection of a compound of formula (V):

wherein Ri, R₂, R₃, R₄, R₅ and are as defined above, and P is a suitable hydroxyl protecting group.

17. A process for preparing a compound of formula (V) from the corresponding 17α-hydroxyl derivative of formula (VI):

wherein Ri, R₃₎ R₄, R₅ and — are as defined above by acylation with a carboxylic acid of formula (IV) or an activated derivative thereof.

18. A process for preparing a compound of formula (I) which comprises rearrangement of 21-esters of formula (VIII):

wherein R₂, R3, R4, 5 and are as defined in any one of claims 1 to 4.

19. A process of formula (I) which comprises hydrolysis of cyclic orthoesters of formula (X):

wherein R₂, R3, R4, R5 and are as defined in any one of claims 1 to 4 and Re is Cι to C₆ alkyl group.